The present invention relates to an approach for relieving pain and for treating behavioral and perceptive abnormalities, by using myoblast transfer therapy to provide a long-term, continuous supply of peptides in vivo that have analgesic activity.
Modern analgesia theory advanced significantly with a proposal by Pomeranz et al., Exp. Neurol. 54: 172 (1977), that a morphine-like, pituitary peptide mediates acupuncture analgesia. Electroacupuncture was found to reduce responses in spinal cord neurons to noxious stimuli in anesthetized cats and to increase squeak threshold in awake mice. The observed, prolonged time course implicated a hormonal mechanism for the response. Spinal transaction, decerebration or hypophysectomy eliminated this acupuncture effect, and intravenous injections of naloxone, a morphine antagonist, also reduced it markedly.
These results indicate that electroacupuncture stimulates sensory nerves which activate the pituitary glands to release morphine-like hormones (peptides) effecting prolonged reduction in transmission along nociceptive pathways. This mechanism is believed to be a principal mediator of generalized and localized analgesia.
Morphine-like peptides have been identified, and receptors to morphine-like peptides and to other opioid peptides have been found in the brain, the gut, the pituitary gland, the pancreas and the placenta. Hughes et al., Nature 258: 577 (1975); Pert et al., Science 179: 1011 (1979). These peptides now are known as β-endorphins and enkephalins. Cooper et al., THE BIOCHEMICAL BASIS OF PHARMACOLOGY, 4th ed. (Oxford University Press, New York 1982). Furthermore, stimulation of brain neurons with an opioid peptide such as an endorphin produces analgesia. Fields et al., Ann. Rev. Physiol. 40: 217 (1978). This effect can be reversed by naloxone.
Opioid peptides, especially β-endorphins, are essentially neural hormones or transmitters which reach all body tissue through diffusion. The presence of endorphin receptors in large numbers at different areas of the diencephalon and cerebral cortex suggests that the conjugate opioid peptides play a role in analgesia which goes beyond chat of a simple modulator of pain perception. Covenas et al. Neuropeptides 30: 261 (1996); Bernstein et al., Neurosci. Lett. 215: 33 (1996); Bianchi et al., Brain Res. Bull. 40: 269 (1996). Indeed, increases in cerebrospinal fluid and plasma levels of β-endorphins have been shown to modulate and optimize behavioral patterns exhibited in patients suffering from stress, psychiatric disorders, alcoholism, drug addition, obesity, and diabetes. Ryu et al., Am. J. Chin. Med. 24: 193 (1996); Odagiri et al., Int. J. Sports Med. 17: 325 (1996); Dalayeun et al., Biomed. Pharmacother. 47: 311 (1993); Gianoulakis et al., J. Psychiatry Neurosci. 18: 148 (1993). These increases also promote natural killer cell mediated cytotoxicity. Jonsdottir et al., Regul. Pept. 23: 113 (1996); Sacerdote et al., Regul. Pept. 63: 79 (1996).
Analgesia also is affected by binding of a pain mediator called “substance P” to its receptor. There are many similarities between the terminals of opioid neurons and the terminals of substance P sensitive neurons. For example, both types of terminals mediate pain sensation in the spinal cord. Jessel et al., Nature 268: 549 (1977). As indicated, for example, in Japanese patent document JP 3133998, substance P receptors have been shown to act as analgesics by masking the activity of substance P. According to PCT application WO 92/16547, the NK-1 receptor preferentially binds substance P and can be used to treat pain, inflammatory disease, mental illness and stress.
Patients afflicted with conditions such as stress, psychiatric disorders, alcoholism, drug addition, obesity, and diabetes may obtain some measure of relief from an above-normal level of endogenous opioid peptides in their plasma. Clinical relief of symptoms of these conditions have been associated with the binding of opioid peptides with their receptors, which is directly correlated with the level of opioid peptides in the patient's plasma and cerebrospinal fluid. Patients also may benefit from increased levels of substance P receptors or substance P analogs. See WO 92/16547, supra, and PCT application WO 91/02745. To date, no adverse reaction has been associated with physiological increases in plasma or cerebrospinal fluid levels of β-endorphins, enkephalins or substance P receptors.
The use of drugs to increase the production and/or secretion of opioid peptides may provide temporary relief, but uncontrollable drug metabolism and rough dosage eventually will overtax the “sick” neurons and their counterparts. Furthermore, the side effects of drugs are numerous and undesirable. Opioid peptides themselves and opioid peptide receptors have been administered as sedatives and analgesics, see U.S. Pat. No. 4,123,523, but the effects of such administrations are short-lived.
Xenogeneic tumor cells secreting β-endorphin have been transplanted into spinal cord cerebro-spinal fluid space of rats, producing analgesic effects. Saitoh et al., Cell Trans. 4 (Supp. 1): S13-7 (1995). The transplanted cells were reported to survive for one month, and in vitro studies indicated that the cells would secrete β-endorphin for one month. AtT-20 cells and AtT-20/hENK cells, which secrete β-endorphin and enkephalin, respectively, were implanted into mouse spinal subarachnoid space to investigate their use as a therapy for pain. Wu et al., J. Neurosci. 14 (8): 4806 (1994); J. Neural Transplant. Plast. 4 (1): 15 (1993). But these procedures are very invasive and therefore very dangerous, since they involve the transplantation of cells directly into cerebrospinal fluid or spinal subarachnoid space. Also, only a limited number of cells are transplanted, making the amount of opioid peptide provided by these methods limited.
A need therefore exists for a method of long term analgesia by supplying a peptide that binds to opioid receptors or that interferes with binding of substance P to its receptors in vivo over a long time period. Such a method would be useful for treating chronic pain and psychiatric conditions that involve abnormal perception, such as depression, chronic anxiety syndromes, paranoia, alcoholism, and drug addiction, and other diseases in which opioid neurons and substance P terminals play a role.